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European Medicines Agency
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E-mail: mail@emea.europa.eu http://www.emea.europa.eu
©EMEA 2007 Reproduction and/or distribution of this document is authorised for non commercial purposes only provided the EMEA is acknowledged
London, 13 December 2007
Doc. Ref. EMEA/CHMP/BMWP/14327/2006
COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE
(CHMP)
GUIDELINE ON IMMUNOGENICITY ASSESSMENT OF BIOTECHNOLOGY-DERIVED
THERAPEUTIC PROTEINS
DRAFT AGREED BY BMWP
July 2006
ADOPTION BY CHMP FOR RELEASE FOR CONSULTATION
January 2007
END OF CONSULTATION (DEADLINE FOR COMMENTS)
July 2007
AGREED BY BMWP
October 2007
ADOPTION BY CHMP
December 2007
DATE FOR COMING INTO EFFECT
April 2008
KEYWORDS Immunogenicity, unwanted immune response, biotechnology derived
proteins, immunogenicity risk factors, assays, clinical efficacy and safety,
risk management
©EMEA 2007 Page 2/18
GUIDELINE ON IMMUNOGENICITY ASSESSMENT OF BIOTECHNOLOGY-DERIVED
THERAPEUTIC PROTEINS
TABLE OF CONTENTS
EXECUTIVE SUMMARY 3
1.
INTRODUCTION 3
2.
SCOPE 4
3.
LEGAL BASIS 4
4.
MAIN GUIDELINE TEXT 4
4.1
F
ACTORS THAT MAY INFLUENCE THE DEVELOPMENT OF AN IMMUNE RESPONSE AGAINST A
THERAPEUTIC PROTEIN
4
4.1.1
Patient- and disease-related factors 4
4.1.2.
Product related risk factors of immunogenicity 6
4.2
N
ON
-
CLINICAL ASSESSMENT OF IMMUNOGENICITY AND ITS CONSEQUENCES
7
4.3
D
EVELOPMENT OF ASSAYS FOR DETECTING AND MEASURING IMMUNE RESPONSES IN
HUMANS
7
4.3.1
Assay strategy 7
4.3.2
Antibody assays 7
4.3.3
Assay validation 8
4.3.4
Characterisation of antibodies to a therapeutic protein 9
4.4
P
OTENTIAL CLINICAL CONSEQUENCES OF IMMUNOGENICITY
10
4.4.1
Consequences on Efficacy 10
4.4.2
Consequences on Safety 10
4.5
I
MMUNOGENICITY AND
C
LINICAL
D
EVELOPMENT
11
4.5.1
Rationale for sampling schedule and kinetics of the antibody response 11
4.5.2
Consequences on pharmacokinetics of the product 12
4.5.3
Methodology aspects to assess comparability of immunogenicity potential as part of a
comparability exercise 12
4.5.4
Immunogenicity in paediatric indications 13
4.6
R
ISK MANAGEMENT
P
LAN
13
REFERENCES 14
ANNEX 1 FURTHER DETAILS ON METHODS FOR ASSESSMENT AND
CHARACTERISATION OF IMMUNOGENICITY 15
ANNEX 2 AN EXAMPLE OF A STRATEGY FOR ANTIBODY DETECTION AND
CHARACTERISATION 18
©EMEA 2007 Page 3/18
EXECUTIVE SUMMARY
The number of biological/biotechnology-derived proteins used as therapeutic agents is steadily
increasing. These products may induce an unwanted immune response in treated patients, which can
be influenced by various factors, including patient-/disease-related factors and product-related factors.
This document contains background information concerning the potential causes and impacts of
immunogenicity and provides general recommendations for the performance of a systematic
immunogenicity assessment from a marketing authorisation perspective.
The predictive value of non-clinical studies for evaluation of immunogenicity of a biological
medicinal product in humans is low due to inevitable immunogenicity of human proteins in animals.
While non-clinical studies aimed at predicting immunogenicity in humans are normally not required,
animal models may for example be of value in evaluating the consequences of an immune response.
It is essential to adopt an appropriate strategy for the development of adequate screening and
confirmatory assays to measure an immune response against a therapeutic protein. Assays may need to
be capable of distinguishing neutralizing from non-neutralizing antibodies, and for use in pivotal
clinical trials as well as in post-authorisation studies to be validated.
In the clinical setting, careful planning of immunogenicity evaluation should include data
systematically collected from a sufficient number of patients. For a given product, sampling should
preferably be standardized across studies (e.g., sampling at baseline, under treatment and follow up
samples). The sampling schedule for each product is determined on a case-by-case basis, taking into
account also the risks associated with an unwanted immune response to patients. Data on the impact
on efficacy and safety should be collected in order to fully understand the clinical consequences of the
immune response. Immunogenicity issues should be further addressed in the Risk Management Plan.
The scope of this guideline covers a wide applicability. Thus, the concepts might have to be adapted
on a case-by-case basis to fit an individual development programme. Applicants should consider the
possibility to seek Scientific Advice from EMEA or from National Competent Authorities.
1. INTRODUCTION
Most biological/biotechnology-derived proteins induce an unwanted immune response that is triggered
by more than one single factor. This immunological response is complex and, in addition to antibody
formation, other events such as T cell activation or innate immune response activation could
contribute to potential adverse responses.
The consequences of an immune reaction to a therapeutic protein range from transient appearance of
antibodies without any clinical significance to severe life-threatening conditions. Potential clinical
consequences of an unwanted immune response are a loss of efficacy of the therapeutic protein,
serious general immune effects such as anaphylaxis, and, for therapeutic proteins used for substitution,
a potential cross-reactivity with the endogenous counterpart in case it is still produced.
Many factors may influence the immunogenicity of therapeutic proteins. They can be considered to be
patient-, disease- or product-related. Patient-related factors that might predispose an individual to an
immune response include: underlying disease, genetic background, immune status, including
immunomodulating therapy, and dosing schedule. Product-related factors also influence the likelihood
of an immune response, e.g. the manufacturing process, formulation, and stability characteristics.
Although data on possible unwanted immune reactions to therapeutic proteins are required before
marketing authorisation, problems may still be encountered in the post-authorisation period. In the
marketing authorisation application, the applicant should include a summary of investigations of
immunogenicity in the respective overview sections with full cross-reference to the data in the
relevant modules. Depending on the immunogenic potential of the therapeutic protein and the rarity of
the disease, the extent of immunogenicity data before approval might be limited. Further systematic
immunogenicity testing might become necessary after marketing authorization, and may be included
in the risk management plan.
©EMEA 2007 Page 4/18
2. SCOPE
The general principles adopted and explained in this document mainly apply to the development of an
unwanted immune response against a therapeutic protein in patients and how to systematically
evaluate this. The guideline applies to proteins and polypeptides, their derivatives, and products of
which they are components, e.g., conjugates. These proteins and polypeptides are mainly produced
from recombinant or non-recombinant expression systems. Throughout this guideline, the term
“therapeutic protein” is used. This guideline should be read in conjunction with other relevant
guidelines, e.g.:
• Guidelines on similar biological (biosimilar) medicinal products;
• Guidelines on comparability of biotechnology-derived medicinal products after a change in
the manufacturing process.
For coagulation factors, please, refer to the specific CHMP guidelines in this area (see references).
3. LEGAL BASIS
This guideline has to be read in conjunction with the introduction and general principles (4) and part
III of the Annex I to Directive 2001/83 as amended.
4. MAIN GUIDELINE TEXT
The consequences of an immune reaction to a therapeutic protein range from transient appearance of
antibodies without any clinical significance to severe life threatening conditions. As a rule, therapeutic
proteins should be seen as individual products, and experience from related proteins can only be
considered supportive. Also in this respect, concomitant medications and other patient-related factors
like the underlying disease have to be taken into account, since these can also influence the clinical
presentation of immunogenicity. Therefore, immunogenicity evaluation needs to be studied
individually for each indication/patient population.
Evaluation of immunogenicity should be a multidisciplinary task, encompassing joint efforts of
quality, non-clinical and clinical experts.
This document gives general recommendations and principles for developers and assessors of
biotechnology-derived therapeutic proteins of how to approach immunogenicity evaluation from a
marketing authorisation perspective. The scope of this guideline covers a wide applicability. Thus, the
concepts might have to be adapted on a case-by-case basis to fit an individual development
programme. For the justification of their approach to immunogenicity testing, Applicants should take
into consideration both the risk for developing an unwanted immune response, and the potential
clinical consequences as outlined below. The approach taken for the design of the immunogenicity
development concept should be fully justified, e.g. when omitting assays or immune response
measurements proposed in this guideline. Applicants should consider the possibility to seek Scientific
Advice from EMEA or from National Competent Authorities.
4.1 Factors that may influence the development of an immune response against a
therapeutic protein
4.1.1 Patient- and disease-related factors
Patient-related factors, which might influence the immune response to a therapeutic protein, may
include genetic factors, age of the patient, disease-related factors including other treatments, and
previous exposure to similar proteins.
• Genetic factors modulating the immune response
Genetic factors can alter the immune response to a therapeutic protein and lead to inter-patient
variability. Allelic polymorphism in the major histocompatibility complex (MHC), impacting on
affinity and stability of the interaction between MHC molecules and antigenic peptides, and genes
©EMEA 2007 Page 5/18
encoding the T cell receptor of helper T cells may influence immune responses and immunological
tolerance induction.
Immune responses may occur even if the amino acid sequence of the therapeutic protein is fully
human.
Other genetic factors influencing immunogenicity could be gene polymorphisms for cytokines that
play a role in the fine-tuning of the immune response (e.g. interleukin-10, TGF-beta etc.).
• Genetic factors related to a gene defect
If the therapeutic protein is used for substitution of an endogenous protein, reduced levels or even the
lack of this protein may influence immunological tolerance, since for these patients the physiological
antigen may represent a neo-antigen.
• Age
The data from one age group cannot necessarily be projected to others since immune response against
a therapeutic protein can be an age-related phenomenon. Children may possibly have a different
immune response to these proteins. If the product is indicated in children, studies on immunogenicity
should be carried out in this age group (see section 4.5.4). If indicated in elderly, consideration should
be given to a potentially altered immune response.
• Disease-related factors
The patient’s underlying disease itself can be an important factor in the context of developing an
unwanted immune response.
Some patients with chronic infections may be more prone to an immune response, since their immune
system is in an activated state.
In other conditions (e.g. malnutrition, advanced metastatic disease, advanced HIV disease, organ
failure), an immune response against a therapeutic protein might be less likely to occur due to an
impaired immune system.
For some products, it has been reported that the development of an antibody response can be different
for different therapeutic indications or different stages of the disease. Therefore, immunogenicity
normally needs to be studied separately for each disease or stage of the disease as part of the clinical
studies.
• Concomitant treatment
Concomitant therapies may either decrease or increase the risk of an immune response to a therapeutic
protein. Typically, the immune reaction against a therapeutic protein is reduced when
immunosuppressive agents are used concomitantly. Consideration should also be given to previous
treatments, that can modulate the immune reaction to a therapeutic protein and that have a long-term
impact on the immune system. If clinical trials are performed in combination with
immunosuppressants, a claim for use of the therapeutic protein in monotherapy must be accompanied
by adequate clinical data on the immunogenicity profile in absence of immunosuppressants, i.e.
immunogenicity data from the combination with immunosuppressants are not relevant for the
monotherapy setting.
• Duration, route of administration, treatment modalities
Factors which may increase the immune response to a therapeutic protein may be the route of
administration, dose, and the schedule of administration.
Products given intravenously may be less immunogenic than those given subcutaneously or
intramuscularly.
Short-term treatment only is usually less likely to be associated with immune response than long-term
treatment, and products given continuously are usually less immunogenic than those given
intermittently.
©EMEA 2007 Page 6/18
Intermittent treatment or re-exposure after a long treatment free interval may be associated with an
enhanced immune response.
• Previous exposure to similar or related proteins
Previous exposure to similar or related proteins can lead to pre-sensitisation and cause an immune
response. For certain proteins being used for replacement therapy, previous therapies may have
induced cross-reacting antibodies or immunological memory that affects subsequent therapies.
4.1.2. Product related risk factors of immunogenicity
Product-related factors influencing the immunogenicity of biological/biotechnology-derived
therapeutic proteins include the origin and nature of the active substance (structural homology, post-
translational modifications), modification of the native protein (e.g. pegylation), product- and process-
related impurities (e.g. breakdown products, aggregates and host cell proteins, lipids or DNA), and
formulation.
• Protein structure
Biotechnology-derived analogs to human endogenous proteins may trigger an immune response due to
variations in the amino acid sequence or changes to the protein structure as a result of post-
translational modifications, physical, chemical or enzymatic degradation and/or modification e.g.
deamidation, oxidation and sulfatation during all steps of the manufacturing process and during
storage. Fusion proteins composed of a foreign and self-protein are of particular concern because of
the potential of the foreign moiety to provoke an immune response to the self-protein (epitope-
spreading). Identification of the antigenic moiety of the fusion protein is advisable. Glycosylation is a
frequent posttranslational modification of biotechnology-derived therapeutic proteins. These
modifications may differ in the number and position of glycosylation sites as well as sequence, chain
length and branching of the attached oligosaccharide. Therefore, when the same protein is
manufactured under different conditions (e.g. change in cell culture process) there might be changes in
the pattern of post-translational modifications and the immunogenic potential of the protein. This
means also that antibodies induced by one product may react differently with the analogous product
manufactured under modified conditions. This might have to be considered for evaluation of
immunogenicity.
• Formulation
The composition of a formulation is chosen in order to best maintain the native conformation of
therapeutic proteins. A successful, robust formulation depends on the understanding of the physical
and chemical nature of the active substance and the excipients alone and their interaction. The
formulation and the source of excipients may alter immunogenicty of therapeutic proteins and should
be considered as a possible cause of such events. This should be considered when variations to the
formulation are made.
Impact of the primary packaging material and the conditions of clinical use e.g. dilution in infusion
solutions and infusion devices of different materials could also influence the immunogenic potential of
a therapeutic protein.
• Aggregation and Adduct Formation
Aggregation or adduct formation of proteins may either reveal new epitopes or lead to the formation
of multivalent epitopes, which may stimulate the immune system. Factors which could be considered
to contribute to aggregate or adduct formation include formulation, purification processes, viral
inactivation procedures, and storage conditions of intermediates and finished product. The use of
proteins, e.g. albumin, as excipient may lead to the formation of more immunogenic aggregates. It is
important to monitor the aggregate and adduct content of a product throughout its shelf life.
• Impurities
There are a number of impurities of therapeutic proteins, which potentially can serve as adjuvants.
Host cell proteins (HCPs) from the cell substrate co-purified with the active substance could induce
©EMEA 2007 Page 7/18
immune responses against themselves. But it is also possible that these HCPs, host cell-derived lipids
or DNA function as adjuvants for the protein of interest.
4.2 Non-clinical assessment of immunogenicity and its consequences
Therapeutic proteins show species differences in most cases. Thus, human proteins will be recognised
as foreign proteins by animals. For this reason, the predictivity of non-clinical studies for evaluation of
immunogenicity is considered low. Non-clinical studies aiming at predicting immunogenicity in
humans are normally not required. However, ongoing consideration should be given to the use of
emerging technologies (novel in vivo, in vitro and in silico models), which might be used as tools.
Measurement of antibodies in non-clinical studies are however requested as part of repeated dose
toxicity studies, in order to aid in the interpretation of these studies (as discussed in “Note for
guidance on preclinical safety evaluation of biotechnology-derived pharmaceuticals.” ICH S 6).
Also, the comparison of the antibody response to the reference product in an animal model may be
part of the comparability exercise both for similar biological medicinal products (see Guideline on
Similar biological medicinal products containing biotechnology-derived proteins as active substance:
Non-clinical and clinical issues CHMP/42831/05 and product-specific annexes) and for changes in
manufacturing processes (see Guideline on comparability of biotechnology-derived medicinal
products after a change in the manufacturing process – Non-clinical and clinical issues
CHMP/BMWP/202695/06).
An immune response to a therapeutic protein representing a counterpart to an endogenous protein may
result in cross-reactivity, directed to the endogenous protein in cases where endogenous protein is still
produced. Any relevant experience on the consequences of induction of an immune response to the
endogenous protein or its absence/dysfunction in animal models should be discussed. Both humoral
and cellular immune responses (where relevant) should be considered. In absence of such data, and if
theoretical considerations are suggestive of a safety risk, animal immunisation studies with the
therapeutic protein or the animal homolog may be considered in order to gain information on the
potential consequences of an unwanted immune response.
4.3 Development of assays for detecting and measuring immune responses in humans.
Unwanted immunogenicity induced by biologicals can comprise humoral and cellular immune
responses. It is therefore very important to select and/or develop assays and assay strategies for
assessment of such immune responses. Most effort is usually focused on antibody detection and
characterisation, as this is technically feasible and often related to clinical safety and efficacy.
However, cell-mediated responses could play an important role and their assessment may be
considered by applicants on a case by case basis.
4.3.1 Assay strategy
Adopting an appropriate strategy for assessment of unwanted immunogenicity of biological products
is essential. This should usually include a screening assay for identification of antibody positive
samples/patients, analytical immunochemical procedures for confirming the presence of antibodies
and determining antibody specificity and functional assays for the assessment of the neutralizing
capacity of antibodies. In addition, non-antibody assays e.g., assays for relevant biomarkers or
pharmacokinetic measurements will be required which assess and characterize the clinical impact of
antibodies (and possibly other components of immune responses) if these are detected/induced. It is
important to include baseline data from all patients where appropriate.
Annex 2 shows an example of a possible strategy for antibody detection and characterisation.
4.3.2 Antibody assays
• Screening assays
A screening assay should be capable of detecting antibodies induced against the biological product in
all antibody positive samples/patients. This implies that detection of some false positive results is
inevitable as absolute screening-assay specificity is normally unattainable and false negative results
©EMEA 2007 Page 8/18
must be avoided. The desirable characteristics of screening assays are sensitivity, specificity,
precision, reproducibility and robustness.
• Assays for confirming the presence of antibodies
These assays are necessary for elimination of false positive samples/patients following the initial
screen. Various approaches can be adopted for this purpose but it is necessary to select assays taking
account of the limitations and characteristics of the screening assay(s). To confirm specificity, it is not
normally sufficient or appropriate to simply repeat the screening assay in its original form.
• Assays for dissecting the specificity of antibodies
Assays which provide information concerning the specificity of the antibodies detected may be useful
in some cases. This data contributes to confirmation of the specificity of the immune response.
• Neutralization assays
Assessing the neutralizing capacity of antibodies usually requires the use of bioassays. An assay must
be selected or developed which responds well to the biological product. Bioassays used for measuring
the potency of biological products e.g. for lot release purposes can often be adapted to assess
neutralising antibodies. However, they frequently require refining if they are to perform optimally for
measuring the neutralizing capacity of antibodies. If neutralising cell-based assays are not
feasible/available, competitive ligand binding assays or other alternatives may be suitable. However,
when these are used it must be demonstrated that they reflect neutralizing capacity/potential in an
appropriate manner.
4.3.3 Assay validation
Assay validation is an ongoing process throughout product development. Assays used for the pivotal
clinical trials need to be validated for their intended purpose. Validation studies must be conducted to
establish that the assays show appropriately linear, concentration dependent responses to relevant
analytes as well as appropriate accuracy, precision, sensitivity, specificity and robustness. For pivotal
clinical trials, the use of a central laboratory to perform the assays may be helpful to avoid inter-
laboratory variability. In the post-approval setting, it is also important to consider inter-laboratory
variability.
Assays must also be validated to show that matrix effects caused by reagents or substances present in
samples do not adversely affect the results obtained. This is normally addressed by ‘recovery’
investigations conducted by observing the effects of such substances present in the matrix on the
response obtained in their absence. This needs to be investigated for the full range of dilutions of
samples, which are to be used in assays, and, at least in some cases, limits the dilutions, which can be
validly assessed.
Residual biological product present in patients’ blood can complex with induced antibody and hence
reduce the amount of antibody detectable by assays. This may affect assays differently, depending on
the assay, assay format or type and the antibody characteristics. If this occurs, it may be
circumvented/resolved by using a number of approaches e.g. by dissociating the immune-complexes
with acid, removing excess biological by solid-phase adsorption, use of long incubation times and/or
using an assay which allows sufficient sample dilution to avoid this problem. Such approaches must
themselves be validated for effectiveness and adopted on a case-by-case basis according to needs. In
some cases this problem can be overcome by appropriate spacing of the timing between administration
of product and sampling for antibody assessment i.e. allowing time for the product to be cleared from
the circulation before sampling. However this latter approach must not significantly compromise the
detection of antibodies or the treatment of the patient.
• Standardisation and controls
Assays must be standardised and this requires the identification and/or development of appropriate
reference materials, i.e. the use of relevant biological standards and/or well characterized positive and
negative controls. These reagents function as critical assay reagents and are essential for assay
©EMEA 2007 Page 9/18
calibration and validation. This is especially important for assays used in unwanted immunogenicity
investigations/studies, as it is intimately associated with assay interpretation and with distinguishing
antibody positive from antibody negative samples.
4.3.4 Characterisation of antibodies to a therapeutic protein
If antibodies are detected in patients undergoing therapy, these need to be characterized to establish
their clinical significance. This normally involves an immunological and/or biological assessment of
antibody characteristics and investigation of effects of the antibodies (or other induced immune
responses) on the product. Some of this can be addressed by non antibody assays as part of in vitro
studies but it may also require clinical assessment of the patients receiving therapy.
• Antibody Characteristics
If antibodies are induced in patients, serum or plasma samples need to be characterised in terms of
antibody content (concentration/titre), neutralizing capacity and possibly other criteria determined on a
case-by-case basis according to the biological product, the type of patients treated, the aim of the
study, clinical symptoms and possibly other factors. These may include antibody class and subclass
(isotype), affinity, specificity. The degree of characterization required may differ depending on the
study purpose and stage of development of the product. The assays used should be qualified for their
intended purpose.
Antibodies present in confirmed positive samples need to be examined for specificity for the active
protein and, where applicable, distinguished from antibodies which bind to product-related and
process-related components. It has been shown that antibodies can be induced against all and or any of
these. It is also useful to screen for cross reactivity with other products based on the particular protein
as well as (if possible and relevant) its endogenous counterpart.
The neutralising capacity of antibodies present in positive samples needs to be established as this often
correlates with diminished clinical responses to biological product. In some cases, screening
neutralizing samples for cross-neutralization of other products based on the same protein and the
endogenous protein is important as it may have implications for clinical efficacy and safety. It should
be noted that neutralizing activity does not necessarily correlate with binding antibody content i.e.
samples containing significant or high amounts of binding antibodies may fail to neutralize biological
activity whereas samples containing lower amounts of binding antibodies can neutralize variable
(sample dependant) amounts. This may depend on product, but must be determined empirically.
• Immunogenicity Assessment strategy –design and interpretation
Immunogenicity studies need to be carefully and prospectively designed to ensure all essential
procedures are in place before commencement of clinical assessment. This includes the selection,
assessment, and characterisation of assays, identification of appropriate sampling points, sample
volumes and sample processing/storage and selection of statistical methods for analysis of data. This
applies to assays used to measure and characterise antibodies and to methods employed for assessing
clinical responses to antibodies if they are induced. Much of this needs to be established on a case-by-
case basis, taking account of product, patients, and expected clinical parameters. Such studies can
provide valuable information concerning significant immunogenicity of biological products, its
characteristics and potential clinical consequences. They can be valuable for comparative
immunogenicity studies for biosimilar products or following production/process changes introduced
for established products. However, unwanted immunogenity can occur at a level, which will not be
detected by such studies when conducted at a pre-approval stage, due to the restricted number of
patients normally available for study. In view of this, it is often necessary to continue assessment of
unwanted immunogenicity and its clinical significance post-approval, usually as part of
pharmacovigilance surveillance. In some cases, post-approval clinical studies may be needed to
establish the risk associated with an unwanted immune response.
For further details on methods for assessment and characterisation of immunogenicity see Annex 1.
©EMEA 2007 Page 10/18
4.4 Potential clinical consequences of immunogenicity
4.4.1 Consequences on Efficacy
Factors which influence whether antibodies to a therapeutic protein will induce clinical consequences
include the epitope recognised, affinity, class of the antibody, the amount of antibodies generated, and
the pharmacological properties of the biotechnological medicinal product. In addition, the ability of
immune complexes to activate complement or be cleared may be a factor that impacts clinical
outcome. Usually, antibodies recognising epitopes on the therapeutic protein not linked to activity are
expected to be associated with less clinical consequences. However, as discussed below, such
antibodies can influence pharmacokinetics and, as such, influence efficacy indirectly. “Neutralising”
antibodies, interfering with biological activity by binding to or near the active site, or by induction of
conformational changes, can induce loss of efficacy. Determination of neutralizing antibodies from
confirmed positives, and the assays used, should be appropriate (see section 4.3). Most importantly,
neutralizing antibody assays should be capable of detecting clinically relevant neutralizing antibodies.
Correlation of antibody characteristics with clinical responses requires a comparison of data generated
in assays assessing antibody responses (see above) with results generated using patients’ samples and
assays designed to assess clinical responses. Most of the latter are product-specific, e.g. assessing
expansion of leukocyte populations by colony-stimulating factors, or increased reticulocyte numbers
by erythropoietin. Such assays need to be selected according to product and need. In many cases, it
might be difficult to identify a clinical endpoint which is sensitive enough to establish the impact on
clinical outcome directly, and adoption of a surrogate measure of response may be an option, e.g.
biomarkers/pharmacodynamic markers. The choice of such markers should be justified. In vivo
comparison of patient’s clinical responses to product before and following antibody induction can
provide information on the correlation between antibody development (and antibody characteristics)
and clinical responses. This can be done either by intra-group analysis (response in patients before and
after occurrence of antibodies), or by comparison with patients within the study who do not show an
immune response.
4.4.2 Consequences on Safety
Loss of efficacy and alteration of the safety profile are not necessarily linked. Safety issues, like
infusion-related reactions, can occur even when there is no loss of efficacy.
• Acute consequences
Usually, patients who develop antibodies are more likely to show infusion-related reactions. Acute
infusion reactions including anaphylactic reactions may develop during (within seconds) or within a
few hours following infusion. Applicants should differentiate between the terms “infusion reaction”
and “anaphylaxis” and carefully define which symptoms to label as “infusion-related reaction”.
“Infusion reactions” usually represent symptoms occurring in a close timely relationship to an infusion
and are not necessarily linked to anaphylaxis or even hypersensitivity. However, acute reactions can
be true allergic, namely IgE-mediated type I reactions (anaphylactic reactions), including hypotension,
bronchospasm, laryngeal or pharyngeal oedema, wheezing and/or urticaria. The term “anaphylaxis”
should be restricted to such situations and represents a strict contraindication to further exposure to the
drug. However, the majority of infusion reactions are characterized by more non-specific symptoms,
for some products more frequently occurring on initial exposure and sometimes less frequent/severe
reactions are observed on re-exposure. An infusion might not represent a contraindication to further
exposure. A range of symptoms including headache, nausea, fever or chills, dizziness, flush, pruritus,
and chest or back pain have been described in relation to infusions. It is acknowledged that the
distinction between an infusion reaction and anaphylaxis can be challenging, but nevertheless such
distinction in necessary due to the different clinical consequence.
Applicants should not only focus on infusion reactions and anaphylactic symptoms since the
consequence of immunogenicity is product-specific and can elicit unexpected clinical symptoms.
[...]... availability of alternative therapies, duration of treatment, etc Pre-authorization immunogenicity findings including impact on efficacy and safety Experience on immunogenicity with similar proteins or related members from that class of proteins, including proteins manufactured with similar production processes Seriousness of the immune reaction However, biotechnology-derived proteins should be considered... medicinal products containing biotechnology-derived proteins as active substance: Non-clinical and clinical issues (CHMP/42831/05) • Guideline on comparability of biotechnology-derived medicinal products after a change in the manufacturing process Non-clinical and clinical issues (CHMP/BMWP/101695/2006) • Guideline on the Clinical Investigation of the Pharmacokinetics of Therapeutic Proteins (CHMP/EWP/89249/2004)... In case of continuous chronic treatment, usually immunogenicity data for one year of treatment should be available pre-authorisation Deviations should be fully justified, e.g shorter exposures or differences as regards the extent of data for different routes of administration If used for different routes of administration, Applicants should justify their approach as regards immunogenicity assessment. .. physicians of how to access specific investigation tools like antibody testing assays); • Monitoring activities to ensure effectiveness of risk minimization Applicants should respond to evolving data on immunogenicity by taking adequate measures, e.g changes in the Product Information, update of the RMP, and other risk minimization activities (e.g educational programmes etc.) For planning immunogenicity assessment. .. route at the time of Marketing Authorisation Application Depending on the medicinal product and the potential risks associated with the occurrence of an unwanted immune response, it might become important to cover a sufficient number of exposures If feasible, sampling should also be done after completion of the treatment regimen to determine persistence of response While a decrease of anti-drug antibodies... described in Section 4.3 as needed A change in pharmacokinetics may be an early indication of antibody formation If antibodies are detected during the clinical programme, their possible interference with the pharmacokinetics should be studied (see also Guideline on the Clinical Investigation of the Pharmacokinetics of Therapeutic Proteins) 4.5.3 Methodology aspects to assess comparability of immunogenicity. .. minimization should follow the principles outlined in this guideline Again, it should be emphasized that evaluation of immunogenicity is a multidisciplinary approach, at best providing input of quality, non-clinical and clinical experts The extent of data on immunogenicity that can be obtained during the clinical development programme of a biotechnology-derived product before approval depends on the event... useful information regarding the nature of the immune response and may contribute to prediction of development of immunogenicity problems Studies using peptides or full-length protein (depending on the assays and purpose of the assays) and Elispot methodologies can be used for these In some cases more complex ©EMEA 2007 Page 15/18 investigations of cell-mediated immunity e.g involving study of regulatory... expression of neutralizing activity in terms of meaningful units of biological activity of product/preparation and also provides information relevant to assay validation If such standards are not available, appropriate inhouse preparations need to be established In many cases it is useful to express the neutralizing capacity of samples in terms of the volume of sample required to neutralize a constant... Identification & Characterisation (e.g case definitions, antibody assays); • Risk Monitoring (e.g specific framework to associate risk with product); • Risk Minimization & Mitigation strategies (e.g plans to restrict to intravenous use where necessary, actions proposed in response to detected risk etc.); • Risk communication (e.g minimization and mitigation messages for patients and physicians, communication
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